The cardinal feature of the immune system lies in its ability to specifically recognize, then "remember" its encounter with a microbe or foreign antigen. Lymphocytes that mature in the thymus (so called, T lymphocytes) recognize antigenic peptides, expressed on the surface of cells with self-MHC (Major Histocompatibility Complex) molecules. When a T-cell recognizes antigen for the first time (naive T-cell), it becomes activated and undergoes rapid cell division and differentiates into effector cells, which eliminate the antigen and memory cells, which persist after the antigen is cleared. Memory T-cells respond vigorously to re-challenge by antigen, and so give protection against recurrent infection. A key to understanding immunological memory is to determine how long-lived, memory T-cells develop and persist after antigen challenge. The precise lineage relationship between memory and effector cells is not well understood. They will use an assay that will allow them to "count" the number of cell divisions that occur after T-cells encounter antigen and differentiate into effector cells. The application will test the ability of different generations of antigen-activated T-cells to give rise to memory cells 70 days after transfer to antigen-free mice. This will allow them to determine whether CD8+ memory T-cells arise from terminally differentiated effector CTLs or from an earlier progenitor. Mature T-cells express T-cell receptors (TCRs), which are weakly reactive to self-peptide/MHC as a result of positive selection in the thymus. The aim will test the hypothesis that the long-term survival and function of T-cells relies on the specific recognition of self-peptide/MHC. The survival of TCR-transgenic CD8+ cells specific for a male antigen (H-Y) or one of two viruses (influenza or Lymphocytic Choriomengitis virus) in transgenic mice which express single, self-peptide/MHC molecules will be tested. The self-peptide requirements for the maintenance of a diverse and functional repertoire of CD8+ T-cells will also be tested in similar experiments. This application will help determine whether self-reactivity, that can sometimes lead to autoimmune disease, is an intrinsic property of the immune system which ensures immunological memory.